This invention relates to hemofiltration methods and hemofiltration devices.
When the kidneys in mammalian subjects fail to remove metabolic waste products from the body, many other organ systems also soon fail, unless the subject is provided with a blood-cleansing treatment. The symptoms which develop as a result of metabolic waste buildup are termed uremia and the severity of these symptoms is proportional to the retention in the blood of metabolic waste products ordinarily excreted by the kidneys, two of the markers for toxic waste products bering urea and creatinine. Various other metabolic products, which can accumulate in the bloodstream, include polypeptides, phenols, amines, guanidine, and a variety of middle molecules in the molecular weight range of 500-5000 daltons. The kidneys also provide electrolyte balance in the body when functioning normally, excreting Na+, K+, H+, Mg2, and Ca2, Clxe2x88x92, HCO3xe2x88x92, PO4xe2x88x923, etc. ions in excess of body needs. When kidney failure occurs, the metabolic waste products will not be excreted and the proper electrolyte balance will not be maintained.
The mechanism the kidney uses for excretion is ultrafiltration, i.e., the formation of a protein-free ultrafiltrate of plasma by means of a hydrostatic pressure versus oncotic pressure gradient that extrudes water and any dissolved small and middle-sized molecules through a semipermeable membrane. This extrusion retains cells and larger proteins in the blood and thereby permits the convective clearance of waste, salts, and ions. In the kidney, the ultrafiltration is followed by partial reabsorption of useful components and excretion of the remainder. Hemodialysis has been routinely available to subjects in renal failure for about the last 30 years and has permitted maintenance of individual patients for decades, often until death (not resulting from renal failure) or until renal transplantation. In contrast to the ultrafiltration mechanism utilized by the kidneys, hemodialysis (dialysis of the blood outside of the body) removes solutes, such as creatinine and urea, from the blood by diffusion down a concentration gradient through a semipermeable membrane. The solutes diffuse across a semipermeable membrane into a second liquid called dialysate. This principle of clearance by diffusion has remained the cornerstone of therapy for kidney failure for the last 30 or so years. To the extent that there have been technical advances they have occurred in the areas of increased blood flow, increased dialysate flow, improved filter characteristics and dialysate composition.
xe2x80x9cHigh efficiency hemodialysisxe2x80x9d is a variant of hemodialysis in which high blood flow rates and high dialysis flow rates are utilized to increase solute clearance. Despite the achievement of high Blood Urea Nitrogen (BUN) clearances from the subject""s blood, high-efficiency dialysis has significant drawbacks. First, this type of treatment is unable to clear so-called xe2x80x9cmiddle moleculesxe2x80x9d from the blood. Middle molecules, as indicated previously, are those with a molecular weight of between 500 and 5000 daltons, and include molecules such as xcex22-microglobulin. The accumulation of xcex22-microglobulin in the blood of patient on long-term hemodialysis is responsible for the incidence of amyloidosis, one of the major sources of morbidity in subjects suffering from renal failure undergoing dialysis. Second, the time for treatment is still considerable. The best dialysis centers, using the most advanced equipment, dialyzing the leanest, most fit patients report, at best, successful treatment times of three hours and the average time is 3.5 hours. The reason for the failure to decrease treatment time further is that patients who undergo rapid hemodialysis report discomfort, not infrequently profound, during and after dialysis treatments. During dialysis, solutes have the opportunity to pass both out of and in to the blood. This occurs because the primary motive force in dialysis is diffusion down a concentration gradient, i.e., diffusion from a compartment of high solute concentration to a compartment of low solute concentration. While current technology provides for highly sterile and relatively pyrogenfree hemodialysis filters and filter cartridges, it is likely that hemodialysis filters and filter cartridges contain traces of compounds which dissolve in the dialysate and diffuse across the filter membrane, into the blood contributing to the discomfort that subjects undergoing dialysis frequently experience.
Convection, the natural mechanism for the renal clearance of solutes from the blood, has been previously employed in dialysis but not fully utilized. Standard hemodialysis uses convection through the process of ultrafiltration, to a very limited degree (only in the context of concomitant diffusion, which provides 99% of the solute clearance), and mainly as a means to reduce interdialysis weight gain. Whereas solute clearance by diffusion is based upon the movement of particles due to the force generated by the concentration gradient of the particles across a semipermeable membrane, convection is based on the movement of particles due to the force generated by the bulk flow of the solvent in which the solute is dissolved. Prior to the present invention, convection had only been used as a minor component in the clearance of solute in standard hemodialysis therapies because any significant degree of bulk flow of water out of the blood compartment will necessarily concentrate the protein constituents of the blood and the resulting increase in oncotic pressure will retard further ultrafiltration. IN addition, concentrating the plasma proteins can promote clotting. These difficulties have been considered by those in the art to be major impediments to large volume hemofiltration ins subjects with end-stage renal disease.
The development of large-pore, high flux blood filters has enabled so-called xe2x80x9chigh flux hemodiafiltration.xe2x80x9d With this method, convection occurs early during the transit of blood through the highly porous filter, i.e., in the part of the filter nearest the blood inlet. Later in the blood""s transit, diffusion clearance predominates, but overall, convection is still a relatively minor component of the solute clearance per treatment. The approximate convection/diffusion ratio with this method, as currently practiced, is approximately 30%, i.e., 30/100.
Hemofiltration refers to the exclusive use of ultrafiltration to convectively clear solutes. A method that uses hemofiltration exclusively for clearing solutes prevents any back-diffusion of plasticizers from filter to blood, thereby avoiding or significantly ameliorating the discomfort that most dialysis subjects experience during and after dialysis. However, in the hemofiltration methods of the prior art the problem of low filtration rates due to the excessive concentration of plasma proteins has resulted in inadequate solute clearance. Predilution, i.e., dilution of the blood before filtration with a volume of an isosmotic solution, has rarely been used in hemofiltration due to the requirement for large volume delivery. An attempt has been made to address the problem of low solute clearance efficiency by the use of multiple filters with post-filter dilution, but the increased equipment and treatment costs associated with use of multiple filters have effectively eliminated this mode of treatment from being used in the United States. Thus, there is a need in the art for a high efficiency hemofiltration device that can function with one filter and that can achieve rapid (i.e., faster) solute clearance from the blood with at least the same efficiency as currently used hemodialysis methods, or that can achieve higher levels of solute clearance in the same treatment time as the systems and devices currently in use. The art is also in need of a hemofiltration system and device that are effective in clearing so called xe2x80x9cmiddle moleculesxe2x80x9d from a xe2x80x9cpatient""s blood.xe2x80x9d
A method and apparatus have now been unexpectedly discovered the efficiently, and with a single filter, clear solutes from the blood of renal disease patients solely by convection. The method comprises the steps of
1. diluting and mixing the blood to be cleared of solute with a non-isosmotic solution;
2. delaying entry of the blood-diluent mixture into the filtering means for a sufficient amount of time to allow diffusion/transport of solutes from the red blood cells in said blood; and
3. filtering the blood-diluent mixture through a single filter means comprising a highly porous membrane, providing for rapid and efficient solute clearance, including clearance of xe2x80x9cmiddle moleculesxe2x80x9d for which dialysis is not effective.
It has now unexpectedly been discovered that mixing blood with a non-isosmotic diluent and allowing the blood to equilibrate with the non-isosmotic diluent is a mixing/detention chamber allows solutes to be transferred from inside the red blood cells of the blood to the plasma/diluent. This increases the effective concentration of solutes in the blood/diluent system that can be cleared by convection, allowing for greater solute clearance from blood in a shorter time period. Further, the red blood cells, after having lost through diffusion or transport quantities of solutes due to equilibration with the non-isosmotic diluent, can then be sent back into the body of the patient, where they can serve as solute xe2x80x9csponges,xe2x80x9d loading up with solutes present in the subject""s blood which will again be extruded the next time the blood cell goes through the hemofiltration apparatus of the invention. These features of the present invention, i.e., causing extrusion of solutes from red blood cells and utilizing red blood cells that have equilibrated with non-isosmotic diluent, overcome the principal deficiency of hemofiltration of blood reported in the prior art, namely the relatively inefficient solute clearance relative to dialysis. Thus, the present invention provides a method for cost and time efficient hemofiltration, with superior results as compared to dialysis, while employing only a single filter.
In a preferred embodiment, the apparatus of the present invention includes a hemofilter, a blood pump for drawing blood from a patient and propelling the blood into a mixing chamber, a mixing and detention chamber where the blood and a non-isosmotic diluent are mixed and are allowed to approach or reach equilibrium (with regard to solute concentration), a mixing element for creating turbulence in the mixing/detention chamber, and suitable tubing for carrying the pumped blood to and from the patient. The system further includes a system for continuous mixing of water and concentrate of diluent thereby maintaining a supply of non-isosmotic diluent, and a diluent pump for pumping the diluent to the appropriate blood tubing access port. Fluid from the hemofilter is moved by pump to waste drainage. The apparatus also contains flow meters for monitoring the flow of fluid into and out of the patient, a line to waste drainage, a mixing chamber, a back pressure valve for controlling the transmembrane pressure in the filter, and a controller operably connected to the blood pump, the diluent pump, and the drainage pump. Also part of the apparatus are means for controlling and determining the amount of diluent added to the subject""s blood and a means for determining the amount of fluid drained from the hemofilter.
The advantages of the apparatus and method of the present invention are achieved at least in part as the result of prediluting the blood to be treated with a non-isosmotic diluent, which provides for increased diffusion and/or transport of solutes from red blood cells, and from the presence and use of a mixing/detention chamber, which allows for solute efflux from the intracellular compartment of red blood cells to the blood plasma/diluent extracellular compartment. These features of the invention permit hemofiltration of blood to be performed in the same or less time than is required for adequate solute removal by dialysis, while maintaining the economy of using a single filter cartridge, and avoiding the recognized intra- and post-treatment side effects of hemodialysis. Further features and advantages of the system and apparatus of the present invention will become apparent with reference to the drawings and the detailed description which follows.